Purpose:

Systemic sclerosis (SSc) is a rare and severe rheumatic disease. Different lines of evidence suggest that genetic factors may underlie not only SSc susceptibility but also the predisposition to develop certain specific disease phenotypes or clinical symptoms such as limited (lcSSc) and diffuse (dcSSc) cutaneous subtypes and the presence of auto-antibodies, such as anti-centromere (ACA) and anti-topoisomerase I (ATA). To assess the genetic component involved in the different SSc subtypes we analyzed genome-wide association (GWAS) data and replication cohorts from the US and Europe in a total of 5,471 Caucasian individuals with SSc and 10,143 healthy Caucasian controls.

Methods:

After all data was quality filtered, 2,296 individuals with SSc and 5,171 healthy controls were analyzed for genetic associations with lcSSc, dcSSc, ACA positive and ATA positive subgroups. SNPs from each subphenotype with a corrected P value lower than 1×10-4 not previously described in the literature were selected for replication. These associations were then analyzed in 9 replication cohorts from US and Europe comprising an additional 3,175 SSc patients and 4971 healthy controls.

Results:

Eighteen non-HLA SNPs were selected from the SSc GWAS analysis. Meta-analysis of all the cohorts (5,471 individuals with SSc and 10,143 healthy controls) showed a strong association of rs11642873 in the IRF8 gene (P = 5.42×1012, OR = 0.75) and a suggestive but consistent association among populations, of rs12540874 in the GRB10 gene (P = 1.31×10-6, OR = 1.15) with the limited subtype of the disease. We also found a strong association of rs11047102 of the SOX5 gene (P = 1.04×10-7, OR = 1.36) with the ACA positive subgroup of patients. In addition to these phenotype dependent associations, we found rs11724804 in the DGKQ gene (P = 1.79×10-6, OR = 1.12), rs1868929 between the AMRC9 and PSMD1 genes (P = 3.27×10-6, OR = 1.27) and rs10275834 in the JAZF1 gene (P = 9.44×10-6, OR = 1.12) to be associated with SSc.

Conclusions:

Outside of the HLA region, we have identified 3 new genes (IRF8, GRB10 and SOX5) associated with clinical manifestations of the disease, emphasizing the differential genetic component of each subphenotype of SSc. We also have identified 3 new genes associated overall with the disease: DGKQ (implicated in cell signal transduction), PSMD1 (the immuno-proteosome subunit which loads immunogenic peptides for MHC transfer) and JAZF1 (a transcriptional repressor previously associated with SLE).